Type: Oral
Session: 721. Clinical Allogeneic Transplantation: Conditioning Regimens, Engraftment, and Acute Transplant Toxicities II
Hematology Disease Topics & Pathways:
Biological, AML, Diseases, Therapies, Combinations, MDS, Myeloid Malignancies, transplantation
Methods: Pts received escalating doses of VEN (dose level (DL)1, 200 mg on Days -8 to -3 (n=3); DL2, 200 mg on Days -8 to -2 (n=3); DL3, 400 mg on Days -8 to -2 (n=16)) in combination with FluBu2 (fludarabine 30 mg/m2/d on Days -5 to -2 and IV busulfan 0.8 mg/kg bid on Days -5 to -2), followed by PBSC infusion on Day 0 and tacrolimus/methotrexate GVHD prophylaxis. Eligible pts included those with adverse risk AML per ELN criteria or secondary AML in complete remission (CR); MDS (t-MDS; Int-2 or higher IPSS; presence of TP53 or RAS pathway gene mutation) or MDS/MPN (including +8; chr 7 abnl; complex karyotype; or ASXL1 mutation) with £10% blasts pre-transplant; and an 8/8 HLA-matched donor. Dose-limiting toxicity (DLT) was defined (first dose of VEN until Day +28) as any treatment-related death, failure to achieve an absolute neutrophil count (ANC) ≥ 500/mL on 2 consecutive occasions, or any gr 4 non-heme toxicity or tumor lysis syndrome. Targeted sequencing of 88 genes on a clinical assay (sensitivity 1-3%) was performed on pre-VEN and day +100 marrow samples. Flow cytometry-based BH3 profiling was performed on pre-VEN treatment bone marrow in pts with measurable residual myeloblasts.
Results: Twenty-two pts (median age 64 y, range 25-71) were treated including 9 AML, 11 MDS, and 2 MDS/MPN cases. 45% of the cohort had an ECOG 2 (n=10). A mutation in TP53 was identified immediately pre-transplant in 55% of pts (n=12). Median HCT-CI score was 4 (range 1-8). 35% and 65.2% had intermediate- and adverse- cytogenetic risk. 20 received HLA-matched unrelated and 2 received HLA-matched related grafts. Median bone marrow leukemia blasts prior to study was 5% (range 5-10). The most common grade 3 or higher non-heme toxicity observed were grade 3 ALT (n=3), diarrhea (n=3), and rash (n=4). Neutrophil engraftment was achieved in all 22 patients (100%). Median days to neutrophil and platelet recovery were 15 (range 12-33) and 14 (range 10-19), respectively. Median donor-derived myeloid chimerism at day +28 was 100% (range, 97-100). No DLTs were observed at DL1-DL3. Acute and chronic GVHD were detected in 12 (GrI, n=7; GrII, n=4; GrIII, n=1) and 6 patients (NIH moderate, n=4; severe, n=2), respectively. At day +100, 16 out of 21 (76%) evaluable patients were in CR. Of the total 22 pts treated to date, 6 have died (5 from disease relapse and 1 from GVHD-related complications). Overall, 7 of 22 pts have relapsed; 2 of these 7 pts subsequently achieved CR2 (one after tapering immunosuppression alone and another after receiving chemotherapy). Median follow-up time among 16 surviving pts is 7.4mo (range, 2.6-19.5). Median OS has not been reached. Median PFS is 11.9 mo (95% CI 6.0 mo, not estimable) (Fig 1). For the entire cohort, the 6-month OS and PFS were 84% and 76%, respectively. Univariable analysis demonstrates pts with an ECOG 0/1 predicted OS and PFS in univariate analysis (p=0.025, 0.001, respectively). Of 21 pts with available paired pre-VEN and day +100 samples, 5 had persistent mutation by NGS (Fig 2). BH3 profiling analysis is underway.
Conclusions: The addition of VEN (400 mg; RP2D) to the backbone of FluBu2 conditioning chemotherapy for allo-HCT is not associated with increased toxicity. VEN/FluBu2 combination demonstrates promising clinical activity supporting further evaluation for high risk disease features. To further reduce disease relapse, we are testing VEN/FluBu2 conditioning chemotherapy with VEN/hypomethylating agent maintenance therapy.
Disclosures: Garcia: Eli Lily: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cutler: Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stone: Astellas: Consultancy; Argenix: Other; Syros: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Other; Daiichi-Sankyo: Consultancy; Syndax: Consultancy, Research Funding; Macrogenics: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Aztra-Zeneca: Consultancy; Jazz: Consultancy; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Biolinerx: Consultancy; Takeda: Other: DSMB; Syntrix: Other: DSMB; Agios: Consultancy, Research Funding; Gemoab: Consultancy; Abbvie: Consultancy, Research Funding. Koreth: EMD Serono: Consultancy; Cugene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Other: Research Support; Equillium: Consultancy; Biolojic Design Inc: Consultancy; Therakos: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Research Support; Amgen: Consultancy; Moderna Therapeutics: Consultancy; Miltenyi: Other: Research Support; Clinigen: Other. Nikiforow: Nkarta Therapeutics: Honoraria; Novartis: Honoraria; Kite/Gilead: Honoraria. Steensma: Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company; Astex Pharmaceuticals, Onconova Therapeutics, Pfizer, Stemline Therapeutics, Summer Road: Consultancy; H3 Biosciences: Research Funding. Letai: AbbVie: Consultancy; AstraZeneca: Consultancy; Chugai: Other; Dialectic: Membership on an entity's Board of Directors or advisory committees; Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Zentalis: Membership on an entity's Board of Directors or advisory committees. Lindsley: Bluebird Bio: Consultancy; Takeda Pharmaceuticals: Consultancy; MedImmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Soiffer: Celgene: Other; Juno: Other; Alexion: Consultancy; Novartis: Consultancy; VOR Biopharma: Consultancy; Mana Therapeutics: Consultancy; Precision Bioscience: Consultancy; Cugene: Consultancy; Rheos Therapeutics: Consultancy; Gilead: Consultancy; Be The Match/National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees. DeAngelo: Amgen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Agios: Consultancy; Glycomimetics: Research Funding; Abbvie: Research Funding; Autolos: Consultancy; Takeda: Consultancy; Forty-Seven: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Jazz: Consultancy; Incyte Corporation: Consultancy; Shire: Consultancy.
OffLabel Disclosure: venetoclax with conditioning chemotherapy in the context of a clinical trial